Project Summary/Abstract Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive loss of memory. Pathological hallmarks of AD include amyloid-beta (A) plaque deposition, neurofibrillary tangle (NFT) formation and the progressive loss of synapses and neurons. A growing literature has indicated that immune activation in the brain, in particular activated microglia may contribute to the progression of AD by facilitating A deposition and NFTs. These findings fit well with the identification of several risk factors in AD are associated with immune and inflammatory pathways. Separate data indicate the endogenous neurotransmitter GABA is capable of modulating activation of microglia and immune function. The identification of mechanisms involved in modulating immune activation in AD may provide valuable insight into disease progression as well as identify novel therapeutic targets. Project 3 will determine the extent to which changes in the GABA transmitter system may be involved in immune activation in AD. We will determine if changes in GABA signaling are related to behavioral impairments and pathological changes in the brain (A, NFT) in an animal model of AD. We will further evaluate the impact of the loss of a specific GABA receptor on microglia in the AD animal model to determine if the immune response in AD is altered. Lastly, we propose to determine if the loss of a specific GABA receptor on microglia exacerbates behavioral and pathological deficits consistent with AD. These data may provide invaluable information for a mechanism to addresses immune activation and the progression of AD.